Biology subjects

Jonker, P. B.

Publications and source records attributed to Jonker, P. B..

3 recordsLinked to original sources

bioRxiv2025

Tumor nutrient stress gives rise to a drug tolerant cell state in pancreatic cancer

Systemic therapies are the standard of care for most pancreatic ductal adenocarcinoma (PDAC) patients but provide limited benefit due to pervasive resistance. The fibrotic tumor microenvironment (TME) is thought to drive resistance by restricting perfusion and drug delivery. Here, we show that therapeutically relevant drug concentrations are achieved even in poorly perfused, therapy-resistant murine PDAC tumors, indicating that impaired delivery alone does not explain drug resistance. Instead, we find TME exposure imprints a therapy-resistant state upon PDAC cells. These observations raised the question of how the TME imposes this state. Poor perfusion alters nutrient availability in the TME. To model this, we developed Tumor Interstitial Fluid Medium (TIFM), which recapitulates TME nutrient conditions. TIFM cultured PDAC cells acquire a therapy-resistant phenotype that mirrors resistance observed in the TME. In this state, cytotoxic and targeted therapies retain on-target activity but fail to trigger cell death, resulting in therapeutic tolerance. Mechanistically, drug tolerance is driven by suppression of apoptotic priming and can be reversed by inhibition of the anti-apoptotic regulator BCL-XL. These results identify TME-driven reprogramming of cell death as a key mechanism of therapy resistance in PDAC and establish TIFM as a physiologically relevant model for studying microenvironment-induced drug resistance.

cancer biology↗

bioRxiv2025

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis

Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors impose metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising antineoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cellular metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1, in part via activation of the amino acid sensor GCN2. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids in cellular membranes. Because of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to polyunsaturated fatty acids, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturated-enriched fats.

cancer biology↗

bioRxiv2022

Pancreatic tumors activate arginine biosynthesis to adapt to myeloid-driven amino acid stress

Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs to maintain survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of murine pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors (Sullivan et al., 2019a). Here, we develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling study of PDAC metabolism under physiological nutrition. We show that PDAC cells cultured in TIFM, compared to standard laboratory models, adopt a cellular state more similar to PDAC cells in tumors. Further, using the TIFM model we identified arginine biosynthesis as a metabolic adaptation PDAC cells engage to cope with microenvironmental arginine starvation driven by myeloid cells in PDAC tumors. Altogether, these data show that nutrient availability in tumors is an important determinant of cancer cell metabolism and behavior, and cell culture models that incorporate physiological nutrient availability have improved fidelity and enable the discovery of novel cancer metabolic phenotypes.

cancer biology↗