Evidence from physical sciences in oncology increasingly suggests that the interplay between the biophysical tumor microenvironment and genetic regulation has significant impact on tumor progression. Especially, tumor cells and the associated stromal cells not only alter their own cytoskeleton and physical properties but also remodel the microenvironment with anomalous physical properties. Together, these altered mechano-omics of tumor tissues and their constituents fundamentally shift the mechanotransduction paradigms in tumorous and stromal cells and activate oncogenic signaling within the neoplastic niche to facilitate tumor progression. However, current findings on tumor biophysics are limited, scattered, and often contradictory in multiple contexts. Systematic understanding of how biophysical cues influence tumor pathophysiology is still lacking. This review discusses recent different schools of findings in tumor biophysics that have arisen from multi-scale mechanobiology and the cutting-edge technologies. These findings range from the molecular and cellular to the whole tissue level and feature functional crosstalk between mechanotransduction and oncogenic signaling. We highlight the potential of these anomalous physical alterations as new therapeutic targets for cancer mechanomedicine. This framework reconciles opposing opinions in the field, proposes new directions for future cancer research, and conceptualizes novel mechanomedicine landscape to overcome the inherent shortcomings of conventional cancer diagnosis and therapies.

Increasingly the significant roles of the interplay between tissue microenvironmental mechanics and cellular biochemical activities during tumor progression have been demonstrated, providing insights into the development of novel cancer therapies.

Electrically excitable cells such as neurons transmit long-distance calcium or electrical signals to regulate their physiological functions. While the molecular underpinnings and down-stream effects of these intercellular communications in excitable cells have been well appreciated, little is known about whether and how non-excitable cancer cells spontaneously initiate and transmit long-distance intercellular signals. Here we report that non-excitable human colon and prostate cancer cells spontaneously initiate and spread intercellular calcium waves, in vitro and ex vivo. Xenograft model studies suggest that these calcium signals promote the growth rate of tumors in mice. Pharmacological studies elucidated that the inositol-trisphosphate-receptor (IP₃R)-regulated calcium release from endoplasmic reticulum (ER), which is activated by the G_q-PLC-IP₃R pathway, is a major cause for the initiation of spontaneous calcium transients. Further, the spatial-temporal characteristics of calcium dynamics can be tuned by the culture substrates of different mechanical stiffnesses. Our results provide evidence that calcium dynamics enables long-distance functional communication in non-excitable cancer cells and offer the potential to modulate calcium signaling for new cancer therapies.

Biomechanical forces are of fundamental importance in biology, diseases, and medicine. Mechanobiology is an emerging interdisciplinary field that studies how biological mechanisms are regulated by biomechanical forces and how physical principles can be leveraged to innovate new therapeutic strategies. This article reviews state-of-the-art mechanobiology knowledge about the yes-associated protein (YAP), a key mechanosensitive protein, and its roles in the development of drug resistance in human cancer. Specifically, the article discusses three topics: how YAP is mechanically regulated in living cells; the molecular mechanobiology mechanisms by which YAP, along with other functional pathways, influences drug resistance of cancer cells (particularly lung cancer cells); and finally, how the mechanical regulation of YAP can influence drug resistance and vice versa. By integrating these topics, we present a unified framework that has the potential to bring theoretical insights into the design of novel mechanomedicines and advance next-generation cancer therapies to suppress tumor progression and metastasis.

Long-range intercellular communication is essential for multicellular biological systems to regulate multiscale cell–cell interactions and maintain life. Growing evidence suggests that intercellular calcium waves (ICWs) act as a class of long-range signals that influence a broad spectrum of cellular functions and behaviors. Importantly, mechanical signals, ranging from single-molecule-scale to tissue-scale in vivo, can initiate and modulate ICWs in addition to relatively well-appreciated biochemical and bioelectrical signals. Despite these recent conceptual and experimental advances, the full nature of underpinning mechanotransduction mechanisms by which cells convert mechanical signals into ICW dynamics remains poorly understood. This review provides a systematic analysis of quantitative ICW dynamics around three main stages: initiation, propagation, and regeneration/relay. We highlight the landscape of upstream molecules and organelles that sense and respond to mechanical stimuli, including mechanosensitive membrane proteins and cytoskeletal machinery. We clarify the roles of downstream molecular networks that mediate signal release, spread, and amplification, including adenosine triphosphate (ATP) release, purinergic receptor activation, and gap junction (GJ) communication. Furthermore, we discuss the broad pathophysiological implications of ICWs, covering pathophysiological processes such as cancer metastasis, tissue repair, and developmental patterning. Finally, we summarize recent advances in optical imaging and artificial intelligence (AI)/machine learning (ML) technologies that reveal the precise spatial-temporal-functional dynamics of ICWs and ATP waves. By synthesizing these insights, we offer a comprehensive framework of ICW mechanobiology and propose new directions for mechano-therapeutic strategies in disease diagnosis, cancer immunotherapies, and drug discovery.