Biology subjects

Driscoll, P. C.

Publications and source records attributed to Driscoll, P. C..

3 recordsLinked to original sources

bioRxiv2025

Lactate Blocks Tertiary Lymphoid Structure Formation by Inhibiting B Cell Chemotaxis

Tertiary lymphoid structures (TLS) and B cell infiltration are strong predictors of immunotherapy success across cancers, including triple-negative breast cancer (TNBC). However, immune-cold TNBCs often lack both features. Here, we identify a tumor-intrinsic mechanism that actively suppresses B cell recruitment. Despite evidence of B cell responses in cancer-associated lymph nodes (cLNs), B cells fail to infiltrate TNBC tumors or form TLS. This exclusion is not simply due to chemokine deficiency as exogenous chemokine addition fails to restore B cell migration. Using fractionation and metabolic profiling, we identify lactate as a dominant tumor-secreted metabolite that directly impairs B cell chemotaxis by disrupting mitochondrial metabolism. In vivo, combining lactate inhibition with engineered chemokine secretion promotes cLN-derived B cell infiltration and enables TLS formation, particularly when coupled with CD40 stimulation. Transcriptomics analyses across several human cancer datasets strengthen the association between high glycolytic activity with poor B-cell infiltration in chemokine-rich tumors. Together, our findings reveal lactate as a key metabolic barrier to B cell trafficking and TLS induction, suggesting that metabolic reprogramming may provide an avenue to convert "immune-cold" tumors into TLS-rich, immunologically responsive microenvironments.

cancer biology↗

bioRxiv2020

Identifying strategies to target the metabolic flexibility of tumours.

Plasticity of cancer metabolism can be a major obstacle for efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify and quantify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in c-MYC-induced liver tumours. We find that glutaminase isoform Gls2, expressed in normal liver, compensates for the deletion of Gls1 isoform expressed in tumours. Inhibiting both glutaminases significantly delays tumourigenesis but does not completely block glutamine catabolism through the Krebs cycle. We reveal that glutamine catabolism is then driven by amidotransferases. Consistently, the synergistic effect of glutaminase and amidotransferase inhibitors on proliferation of mouse and human tumour cells is observed in vitro and in vivo. Furthermore, when Gls1 is deleted the Krebs cycle activity and tumour formation can also be significantly affected if glycolysis is co-inhibited (Gls1KO/Hk2KO). Finally, the inhibition of either serine (Psat1KO) or fatty acid (FasnKO) biosynthesis can be compensated by uptake of circulating nutrients. Thus, removing these nutrients from the diet produces synergistic effects on suppression of tumourigenesis. These results highlight the high flexibility of tumour metabolism and demonstrate how targeting compensatory mechanisms can improve a therapeutic outcome.

cancer biology↗

bioRxiv2018

Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation

Allosteric regulation is central to the role of the glycolytic enzyme pyruvate kinase M2 (PKM2) in cellular metabolism. Multiple activating and inhibitory allosteric ligands regulate PKM2 activity by controlling the equilibrium between high activity tetramers and low activity dimers and monomers. However, it remains elusive how allosteric inputs upon simultaneous binding of different ligands are integrated to regulate PKM2 activity. Here, we show that, in the presence of the allosteric inhibitor L-phenylalanine (Phe), the activator fructose 1,6-bisphosphate (FBP) can induce PKM2 tetramerisation, but fails to maximally increase enzymatic activity. Guided by a new computational framework we developed to identify residues that mediate FBP-induced allostery, we generated two PKM2 mutants, A327S and C358A, in which activation by FBP remains intact but cannot be attenuated by Phe. Our findings demonstrate a role for residues involved in FBP-induced allostery in enabling the integration of allosteric input from Phe and reveal a mechanism that underlies the co-ordinate regulation of PKM2 activity by multiple allosteric ligands.

biochemistry↗