New study reveals key role of Kindlins in cancer treatment pathways

New Delhi: A study has identified the pivotal role of Kindlins—adapter proteins in vertebrate cells—in various cancers, offering potential new avenues for cancer treatment. Conducted by the S. N. Bose National Centre for Basic Sciences in Kolkata, the research highlights how targeting Kindlins could lead to novel treatments that address multiple aspects of cancer simultaneously.

Kindlins, attached to cell membranes, are crucial for transferring extracellular mechanical cues into biochemical signals within cells. These proteins interact with structural proteins, receptors, and transcription factors, triggering vital chemical cascades. Disruptions in Kindlins can significantly impact mechano-chemical signaling, disrupting the body’s homeostasis.

Mutations in Kindlins, often caused by carcinogens like nicotine and ultraviolet rays, can lead to global mechanical homeostasis disruption, promoting cancer cell growth. The study, involving data from 10,000 patients with 33 cancer types from The Cancer Genome Atlas, aimed to unravel these mechanisms.

Led by Debojyoti Chowdhury under Prof. Shubhasis Haldar, the research found that Kindlin 1 regulates the immune microenvironment in breast cancer, while Kindlin 2 governs cancer-specific metabolic regulation, such as the TCA cycle and glycolysis. Kindlin 2 also regulates Hippo signaling, a pathway crucial for cancer cell migration and invasion.

The study, published in Communications Biology, utilized structural and functional genomics tools to investigate Kindlins’ influence on mechano-chemical signaling in various cancers. Results highlighted their role in tumor progression, metastasis, and epithelial-mesenchymal transition (EMT)—a process where cancer cells become more flexible and spread throughout the body.

This structural genomics approach establishes associations with clinical parameters, providing evidence for the potential mechanochemical importance of Kindlins across diverse cancer stages and subtypes. “By studying all Kindlin family members collectively, we can gain a comprehensive understanding of their potential complementary and synergistic roles in cancer biology”, says Chowdhury. “This includes examining the interaction of different Kindlin proteins with each other or with other cellular components to influence cancer cell behavior, tumor progression, and response to therapy”.

“The data related to Kindlin family alternations and mutational and stability analyses presented in our work strongly coincide with those of previous experimental studies. We found that Kindlin 2 expression is elevated in breast cancer, and it activates epithelial-mesenchymal transition (EMT)”, asserts Chowdhury. Similar results had been obtained in earlier experiments too.

The research underscores Kindlins as promising targets for mechano-modulatory cancer therapeutics, presenting new intervention and treatment strategies. By focusing on Kindlins, future therapeutic strategies could tackle chemoresistance and tumor relapse, marking a significant step in the ongoing battle against cancer.