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In the last decades, the role of the microenvironment in tumor progression and therapeutic outcome has gained increasing attention. Cancer-associated fibroblasts (CAFs) have emerged as key players among stromal cells, owing to their abundance in most solid tumors and their diverse tumor-restraining/promoting roles. The interplay between tumor cells and neighboring CAFs takes place by both paracrine signals (cytokines, exosomes and metabolites) or by the multifaceted functions of the surrounding extracellular matrix. Here, we dissect the most recent identified mechanisms underlying CAF-mediated control of tumor progression and therapy resistance, which include induction of the epithelial-to-mesenchymal transition (EMT), activation of survival pathways or stemness-related programs and metabolic reprogramming in tumor cells. Importantly, the recently unveiled heterogeneity in CAFs claims tailored therapeutic efforts aimed at eradicating the specific subset facilitating tumor progression, therapy resistance and relapse. However, despite the large amount of pre-clinical data, much effort is still needed to translate CAF-directed anti-cancer strategies from the bench to the clinic.

Notwithstanding cancer patients benefit from a plethora of therapeutic alternatives, drug resistance remains a critical hurdle. Indeed, the high mortality rate is associated with metastatic disease, which is mostly incurable due to the refractoriness of metastatic cells to current treatments. Increasing data demonstrate that tumors contain a small subpopulation of cancer stem cells (CSCs) able to establish primary tumor and metastasis. CSCs are endowed with multiple treatment resistance capabilities comprising a highly efficient DNA damage repair machinery, the activation of survival pathways, enhanced cellular plasticity, immune evasion and the adaptation to a hostile microenvironment. Due to the presence of distinct cell populations within a tumor, cancer research has to face the major challenge of targeting the intra-tumoral as well as inter-tumoral heterogeneity. Thus, targeting molecular drivers operating in CSCs, in combination with standard treatments, may improve cancer patients' outcomes, yielding long-lasting responses. Here, we report a comprehensive overview on the most significant therapeutic advances that have changed the known paradigms of cancer treatment with a particular emphasis on newly developed compounds that selectively affect the CSC population. Specifically, we are focusing on innovative therapeutic approaches including differentiation therapy, anti-angiogenic compounds, immunotherapy and inhibition of epigenetic enzymes and microenvironmental cues.

By analyzing 26 cases in the EJ Atlas for Sri Lanka, their causes, the impacts, the social actors involved, the forms of mobilization, and the main outcomes of the conflicts, this article examines in what ways activities aiming at economic growth produce socio-environmental conflicts. Such activities increase the social metabolism causing changes that translate into environmental, social, and health impacts which due to inequality of power are unequally distributed. As a result, those who are negatively impacted sometimes mobilize claiming environmental justice. The mining of construction materials to support the boom in the building sector and the expansion of intensive plantations into ‘extraction frontiers’ in new territories, cause deforestation, biodiversity loss, and hurt the local communities. Tourism and industries and new infrastructures are causing displacement, pollution, land degradation, and water shortage, affecting communities of farmers and fishermen that mobilize against the adverse impacts. Those with power to appropriate the natural resources are mostly the state together with international finance institutions and international actors who are able to implement the construction of infrastructures, plantations, and mass tourism. Mobilizations are mostly geared to the protection of livelihoods threatened by loss of access to land, pollution, deforestation, diseases, water scarcity, and new uncertain risks. The protection of the environment demanded by the mobilized groups in Sri Lanka does not aim just to protect nature itself but belongs to a wider movement of an “environmentalism of the poor”.

Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. The cell subpopulation in the lineage hierarchy that serves as cell of origin for the different TC histotypes is unknown. Human embryonic stem cells (hESCs) with appropriate in vitro stimulation undergo sequential differentiation into thyroid progenitor cells (TPCs-day 22), which maturate into thyrocytes (day 30). Here, we create follicular cell-derived TCs of all the different histotypes based on specific genomic alterations delivered by CRISPR-Cas9 in hESC-derived TPCs. Specifically, TPCs harboring BRAF V600E or NRAS Q61R mutations generate papillary or follicular TC, respectively, whereas addition of TP53 R248Q generate undifferentiated TCs. Of note, TCs arise by engineering TPCs, whereas mature thyrocytes have a very limited tumorigenic capacity. The same mutations result in teratocarcinomas when delivered in early differentiating hESCs. Tissue Inhibitor of Metalloproteinase 1 (TIMP1)/Matrix metallopeptidase 9 (MMP9)/Cluster of differentiation 44 (CD44) ternary complex, in cooperation with Kisspeptin receptor (KISS1R), is involved in TC initiation and progression. Increasing radioiodine uptake, KISS1R and TIMP1 targeting may represent a therapeutic adjuvant option for undifferentiated TCs. Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. Here, the authors show the ability of human embryonic stem cells (hESCs) to recapitulate the different TC histotypes upon specific genomic alterations delivered by CRISPR-Cas9 and identify KISS1R and TIMP1 targeting as a therapeutic adjuvant option for undifferentiated TCs.

Background In many tumors, the tumor suppressor TP53 is not mutated, but functionally inactivated. However, mechanisms underlying p53 functional inactivation remain poorly understood. SETD8 is the sole enzyme known to mono-methylate p53 on lysine 382 (p53 K382me1 ), resulting in the inhibition of its pro-apoptotic and growth-arresting functions. Methods We analyzed SETD8 and p53 K382me1 expression in clinical colorectal cancer (CRC) and inflammatory bowel disease (IBD) samples. Histopathological examinations, RNA sequencing, ChIP assay and preclinical in vivo CRC models, were used to assess the functional role of p53 inactivation in tumor cells and immune cell infiltration. Results By integrating bulk RNAseq and scRNAseq approaches in CRC patients, SETD8-mediated p53 regulation resulted the most significantly enriched pathway. p53 K382me1 expression was confined to colorectal cancer stem cells (CR-CSCs) and C1Q + TPP1 + tumor-associated macrophages (TAMs) in CRC patient tissues, with high levels predicting decreased survival probability. TAMs promote p53 functional inactivation in CR-CSCs through IL-6 and MCP-1 secretion and increased levels of CEBPD, which directly binds SETD8 promoter thus enhancing its transcription. The direct binding of C1Q present on macrophages and C1Q receptor (C1QR) present on cancer stem cells mediates the cross-talk between the two cell compartments. As monotherapy, SETD8 genetic and pharmacological (UNC0379) inhibition affects the tumor growth and metastasis formation in CRC mouse avatars, with enhanced effects observed when combined with IL-6 receptor targeting. Conclusions These findings suggest that p53 K382me1 may be an early step in tumor initiation, especially in inflammation-induced CRC, and could serve as a functional biomarker and therapeutic target in adjuvant setting for advanced CRCs. Graphical Abstract

Metastases represent one of the hardest obstacles in cancer treatment, accounting for many cancer-related deaths. Understanding the mechanisms that drive disease progression is essential to improve patient outcomes and develop more effective therapeutic strategies. This phenomenon appears to be elicited by dormant cancer cells (DCCs), which can persist undetected for extended periods of time, entering a non-proliferative, hibernation-like state that confers resistance to conventional therapies and facilitates immune evasion. Owing to their status as a rare and energy-restricted population, combined with the limitations of current medical imaging, DCCs often evade early detection, hindering timely intervention and effective clinical management. Consequently, a critical need exists to develop high-resolution detection systems and identify specific DCC targetable biomarkers. Here, a comprehensive overview of the current understanding of DCCs is reported, with a focus on recent advancements in experimental strategies for their identification and tracking, as well as therapeutic approaches currently under clinical investigation aimed at targeting these elusive cells.

Background The use of stem cells, including mesenchymal stem cells (MSCs), for regenerative medicine is gaining interest for the clinical benefits so far obtained in patients. This study investigates the use of adipose autologous tissue in combination with platelet-rich plasma (PRP) to improve the clinical outcome of patients affected by systemic sclerosis (SSc). Methods Adipose-derived mesenchymal stem cells (AD-MSCs) and PRPs were purified from healthy donors and SSc patients. The multilineage differentiation potential of AD-MSCs and their genotypic–phenotypic features were investigated. A cytokine production profile was evaluated on AD-MSCs and PRPs from both healthy subjects and SSc patients. The adipose tissue-derived cell fraction, the so-called stromal vascular fraction (SVF), was coinjected with PRP in the perioral area of SSc patients. Results Histopathological and phenotypical analysis of adipose tissue from SSc patients revealed a disorganization of its distinct architecture coupled with an altered cell composition. Although AD-MSCs derived from SSc patients showed high multipotency, they failed to sustain a terminally differentiated progeny. Furthermore, SVFs derived from SSc patients differed from healthy donors in their MSC-like traits coupled with an aberrant cytokine production profile. Finally, the administration of PRP in combination with autologous SVF improved buccal’s rhyme, skin elasticity and vascularization for all of the SSc patients enrolled in this study. Conclusions This innovative regenerative therapy could be exploited for the treatment of chronic connective tissue diseases, including SSc.

The tumor microenvironment (TME) plays a key role in promoting and sustaining cancer growth. Adipose tissue (AT), due to its anatomical distribution, is a prevalent component of TME, and contributes to cancer development and progression. Cancer-associated adipocytes (CAAs), reprogrammed by cancer stem cells (CSCs), drive cancer progression by releasing metabolites and inflammatory adipokines. In this review, we highlight the mechanisms underlying the bidirectional crosstalk among CAAs, CSCs, and stromal cells. Moreover, we focus on the recent advances in the therapeutic targeting of adipocyte-released factors as an innovative strategy to counteract cancer progression.

Background Obesity is a recognized risk factor for numerous cancers. Although several biological mechanisms have been proposed to explain obesity-associated carcinogenesis, the extent to which excess adiposity influences tumor genomic profiles remains incompletely understood. In particular, whether obesity-related selective pressures shape cancer-specific mutational landscapes is still underexplored. Methods A pan-cancer analysis of non-synonymous somatic mutations across 14 tumor types using data from The Cancer Genome Atlas (TCGA) has been conducted. Body mass index (BMI) at diagnosis was analyzed as a continuous variable. Associations between gene mutations and BMI were assessed using logistic regression models adjusted for age, sex, and tumor mutational burden, with false discovery rate correction. Genes were prioritized using a two-step ranking strategy based on mutation frequency and regression strength. Functional inactivation, exon-level mutation distribution, and Gene Ontology enrichment analyses were performed for significantly BMI-associated genes. Results In particular, bladder urothelial cancer (BLCA) resulted as the most frequently mutated neoplasia in association with higher body mass index. Among Eighty-six genes significantly associated with BMI in BLCA, a prioritized set of ten genes (BRCA2, DNAH9, GRIA4, PLXNA4, UNC13C, FCGBP, SF3B1, ELP1, NES, TRERF1) has been selected for further analyses. Overweight and obese patients exhibited distinct BMI-specific exon-level mutational patterns and concurrent deleterious mutations across multiple candidate genes. Functional inactivation analysis suggested loss-of-function mechanisms in most top-ranked genes, while Gene Ontology (GO) analysis highlighted deregulation of extracellular matrix–related pathways. Discussion These findings support a role for obesity in shaping the genomic landscape of tumors, highlighting the importance of integrating clinical parameters such as BMI into genomic studies to determine the potential impact of obesity on tumor evolution, heterogeneity, and treatment response.

The green oncology paradigm emphasizes the use of natural products in cancer treatment to protect the environment while reducing the adverse effects associated with conventional therapies. In this context, humic substances (HSs), derived from the degradation of waste biomass, have emerged as promising candidates due to their diverse bioactive properties. Beyond their well-known antioxidant and antimicrobial effects, this study demonstrates the antitumor potential of HSs extracted from olive (HS-OL) and artichoke (HS-CYN). Our results reveal that HS-OL and HS-CYN significantly induce DNA damage by triggering apoptosis and reducing cell viability in cancer cells across various histotypes. When used in combination with standard therapies, these HSs enhance therapeutic efficacy, enabling the use of lower doses of chemotherapeutic agents while maintaining their effectiveness. The introduction of HSs into cancer treatment represents a sustainable and innovative approach that not only reduces the ecological footprint but also minimizes the side effects associated with traditional anticancer drugs, offering a dual benefit for both patients and the environment.