Cancer-associated fibroblasts (CAFs) are part of the tumor microenvironment and can support tumor progression via various mechanisms. CAFs mediate a desmoplastic response in tumors, i.e., they produce and secrete extracellular matrix (ECM), a type of connective tissue cells attach to, which can act as a barrier for the delivery of chemotherapeutics or the infiltration of immune cells into the tumor bed. CAFs also secrete various growth factors and cytokines that can directly promote tumor growth or suppress the activity of immune cells.

The Schwörer Lab is interested in the metabolic control of CAF function in desmoplastic tumors such as pancreatic and breast cancer. Specifically, our research aims to understand how nutrient availability and utilization regulate CAF activation, heterogeneity, and function within tumors. Ultimately, we aim to identify tumor-specific metabolic vulnerabilities in CAFs that could be targeted in combination with chemo- and immunotherapy to improve patient outcomes.

Activation

During cancer initiation, pre-neoplastic cells activate tissue-resident, quiescent fibroblasts or promote the infiltration of mesenchymal precursor cells from other tissues. Compared to the quiescent state, activated fibroblasts are larger, display stress fibers, and begin producing large amounts of ECM. A dramatic remodeling of cellular metabolism accompanies this process. For example, in hepatic and pancreatic carcinoma, tissue-resident stellate cells’ activation results in the loss of lipid droplets. The Schwörer lab aims to understand how the tissue-specific nutrient environment contributes to the activation of fibroblasts. We are specifically interested in this process in metastasis, during which the accumulation of activated fibroblasts is one of the earliest microenvironmental changes upon colonization of a new organ by disseminated cancer cells.

Heterogeneity

The ability of CAFs to engage in various functions that can influence tumor progression has been recognized for decades, and heterogeneity within the CAF population has been known for at least as long. Recent progress in single-cell technology has allowed us to define molecular signatures of multiple CAF subtypes. In the context of earlier findings on tumors growing faster when CAFs were depleted, these findings suggest that this transcriptional heterogeneity translates to functional heterogeneity, such that specific CAF populations promote while others suppress tumor progression. The Schwörer lab has shown that the metabolic features of the tumor microenvironment can dictate the heterogeneity of CAFs in pancreatic cancer (Schwörer et al., 2023, Cancer Research). The lab uses this knowledge to better model CAF heterogeneity in culture, for example, by designing novel systems that allow us to distinguish between these states. We aim to understand better the metabolic programs involved in changing the CAF state during tumor progression and in response to treatment. We also strive to identify additional metabolic features of tumors that impact CAF state decisions and how to manipulate the environment to promote the accumulation of tumor-suppressing CAF populations.

Function

The aberrant synthesis and secretion of ECM is arguably one of the best characterized CAF functions; however, our understanding of how CAFs generate the ECM is limited. The Schwörer Lab investigates how CAFs acquire and use nutrients to create the building blocks for ECM synthesis and how they adapt these processes in the tumor microenvironment that is often deprived of critical nutrients. The lab has elucidated the fibroblast metabolic programs required to increase collagen synthesis in response to TGFβ-induced CAF formation (Schwörer et al., 2020, EMBO Journal). Our work contributed to a better understanding of how CAFs generate proline, which constitutes 25% of all amino acids in collagen: proline is derived from glutamine, and accumulation of mitochondrial NADPH directs glutamine-derived glutamate away from the TCA cycle and into proline synthesis (Schwörer et al., 2020, EMBO Journal; Zhu, Schwörer et al., Science, 2021). However, this process makes CAFs dependent on glutamine, which can be limiting in tumors. In vivo, CAFs use lactate via pyruvate carboxylase to maintain the TCA cycle, such that limiting amounts of glutamine can be used to make proline (Schwörer et al. 2022, Nature Metabolism). The lab seeks to further elucidate the metabolic constraints of ECM synthesis and aims to obtain a holistic understanding of the nutrients fibroblasts use and how they allocate these nutrients to generate the right mix of matrix molecules that help heal a wound but promote tumor growth and metastatic spread.