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"Lyle, Michael"
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Late Miocene decoupling of oceanic warmth and atmospheric carbon dioxide forcing
Measurements from several ocean cores reveal that ocean warmth persisted throughout the late Miocene epoch despite CO
2
levels of only 200–350 p.p.m.v., probably driven by a deep thermocline that isolated climate responses from CO
2
variations.
When ocean temperature and atmospheric carbon dioxide delinked
Geological records of past climate provide the only opportunity to investigate Earth's response to large variations in atmospheric carbon dioxide concentrations. During the late Miocene, between 12 million and 5 million years ago, atmospheric CO
2
levels of only 200 to 350 parts per million by volume were accompanied by almost ice-free conditions in the Northern Hemisphere and the continents were warmer than they are at present, raising questions about the persistence of CO
2
–climate couplings. Using measurements from several ocean cores, LaRiviere
et al
. show that ocean warmth persisted throughout the late Miocene, probably driven by a thick thermocline that isolated climate responses from CO
2
variations. As the depth of the thermocline declined during the late Miocene, the more familiar relationship between CO
2
and climate was established.
Deep-time palaeoclimate studies are vitally important for developing a complete understanding of climate responses to changes in the atmospheric carbon dioxide concentration (that is, the atmospheric partial pressure of CO
2
,
p
CO
2
)
1
. Although past studies have explored these responses during portions of the Cenozoic era (the most recent 65.5 million years (Myr) of Earth history), comparatively little is known about the climate of the late Miocene (∼12–5 Myr ago), an interval with
p
CO
2
values of only 200–350 parts per million by volume but nearly ice-free conditions in the Northern Hemisphere
2
,
3
and warmer-than-modern temperatures on the continents
4
. Here we present quantitative geochemical sea surface temperature estimates from the Miocene mid-latitude North Pacific Ocean, and show that oceanic warmth persisted throughout the interval of low
p
CO
2
∼12–5 Myr ago. We also present new stable isotope measurements from the western equatorial Pacific that, in conjunction with previously published data
5
,
6
,
7
,
8
,
9
,
10
, reveal a long-term trend of thermocline shoaling in the equatorial Pacific since ∼13 Myr ago. We propose that a relatively deep global thermocline, reductions in low-latitude gradients in sea surface temperature, and cloud and water vapour feedbacks may help to explain the warmth of the late Miocene. Additional shoaling of the thermocline after 5 Myr ago probably explains the stronger coupling between
p
CO
2
, sea surface temperatures and climate that is characteristic of the more recent Pliocene and Pleistocene epochs
11
,
12
.
Journal Article
Stroma secreted IL6 selects for “stem-like” population and alters pancreatic tumor microenvironment by reprogramming metabolic pathways
Pancreatic adenocarcinoma is a devastating disease with an abysmal survival rate of 9%. A robust fibro-inflammatory and desmoplastic stroma, characteristic of pancreatic cancer, contribute to the challenges in developing viable therapeutic strategies in this disease. Apart from constricting blood vessels and preventing efficient drug delivery to the tumor, the stroma also contributes to the aggressive biology of cancer along with its immune-evasive microenvironment. In this study, we show that in pancreatic tumors, the developing stroma increases tumor initiation frequency in pancreatic cancer cells in vivo by enriching for CD133 + aggressive “stem-like” cells. Additionally, the stromal fibroblasts secrete IL6 as the major cytokine, increases glycolytic flux in the pancreatic tumor cells, and increases lactate efflux in the microenvironment via activation of the STAT signaling pathway. We also show that the secreted lactate favors activation of M2 macrophages in the tumor microenvironment, which excludes CD8 + T cells in the tumor. Our data additionally confirms that the treatment of pancreatic tumors with anti-IL6 antibody results in tumor regression as well as decreased CD133 + population within the tumor. Furthermore, inhibiting the lactate efflux in the microenvironment reduces M2 macrophages, and makes pancreatic tumors more responsive to anti-PD1 therapy. This suggests that stromal IL6 driven metabolic reprogramming plays a significant role in the development of an immune-evasive microenvironment. In conclusion, our study shows that targeting the metabolic pathways affected by stromal IL6 can make pancreatic tumors amenable to checkpoint inhibitor therapy.
Journal Article