The mechanics of the microenvironment continuously modulates cell functions like growth, survival, apoptosis, differentiation, and morphogenesis via cytoskeletal remodeling and actomyosin contractility 1 – 3 . Although all these processes consume energy 4 , 5 , it is unknown if and how cells adapt their metabolic activity to variable mechanical cues. Here, we report that transfer of human bronchial epithelial cells (HBECs) from stiff to soft substrates causes downregulation of glycolysis via proteasomal degradation of the rate-limiting metabolic enzyme phosphofructokinase (PFK). PFK degradation is triggered by stress fiber disassembly, which releases the PFK-targeting E3 ubiquitin ligase tripartite motif (TRIM)-containing protein 21 (TRIM21). Transformed non-small cell lung cancer cells (NSCLCs), which maintain high glycolytic rates regardless of changing environmental mechanics, retain PFK expression by downregulating TRIM21, and by sequestering residual TRIM21 on a stress fiber population that is insensitive to substrate stiffness. In sum, our data unveil a mechanism by which glycolysis responds to architectural features of the actomyosin cytoskeleton, thus coupling cell metabolism to the mechanical properties of the surrounding tissue. These processes enable normal cells to attune energy production in variable microenvironments, while the resistance of the cytoskeleton to respond to mechanical cues allows high glycolytic rates to persist in cancer cells despite constant alterations of the tumor tissue.

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Tumor-infiltrating B and plasma cells (TIBs) are prevalent in lung adenocarcinoma (LUAD), however they are poorly characterized. We performed paired single-cell RNA and B cell receptor (BCR) sequencing of 16 early-stage LUADs and 47 matching multi-region normal tissues. By integrative analysis of ~50,000 TIBs, we define 12 TIB subsets in the LUAD and adjacent normal ecosystems and demonstrate extensive remodeling of TIBs in LUADs. Memory B cells and plasma cells (PCs) were highly enriched in tumor tissues with more differentiated states and increased frequencies of somatic hypermutation. Smokers exhibited markedly elevated PCs and with distinct differentiation trajectories. BCR clonotype diversity increased but clonality decreased in LUADs, smokers, and with increasing pathologic stage. TIBs were mostly localized within CXCL13+ lymphoid aggregates and immune cell sources of CXCL13 production evolved with LUAD progression and included elevated fractions of CD4 regulatory T-cells. This study provides a spatial landscape of TIBs in early-stage LUAD.

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