Do senescent osteocytes mediate a bone-muscle crosstalk that contribute to musculoskeletal deterioration in colorectal cancer survivors?

• Grant number: 24/04049-9
• Support Opportunities: Scholarships abroad - Research
• Start date: July 15, 2024
• End date: July 14, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Cecilia Helena de Azevedo Gouveia
• Grantee: Cecilia Helena de Azevedo Gouveia
• Host Investigator: Lynda Faye Bonewald
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Indiana University School of Medicine, United States

Abstract

Survivors of colorectal cancer (CRC) frequently present characteristics of enhanced aging, which includes continued musculoskeletal (MSK) deterioration, characterized by muscle atrophy and weakness, along with bone loss and increased risk of fracture, leading to reduced Quality of Life (QoL). Recently, the group of Dr. Lynda F Bonewald has published that the MC38 and C26 CRC cells and chemotherapy cause severe deterioration of the MSK system. In addition, preliminary studies of Dr Bonewald group, using a mouse model of CCR, showed that: (1) factors produced by CRC directly induce senescence in both bone and skeletal muscle; (2) CRC and chemotherapy increases the expression of the cyclin-dependent kinase inhibitors p16 and p21 in bone and muscle, respectively, which are major markers for aging and senescence; (3) the MSK system of 12-month old mice (equivalent to middle age humans) is unable to recover after CRC resection and chemo cessation; (4) senescence markers, including p16, are persistently elevated in the MSK system of a mouse model of CCR survivals; (5) Zoledronate (Za), a bisphosphonate with senomorphic effects, improves the recovery of all the MSK system by reducing senescence in osteocytes. These findings raise the hypotheses that (1) a bone-muscle crosstalk occurs, where senescent osteocytes directly induce bone and muscle deterioration in CRC survivors; and that (2) the reduction of senescence in osteocytes would allow the MSK system to properly regenerate and respond to external stimuli after tumor resection/chemo cessation. The aims of this project are (1) to elucidate the mechanism(s) by which osteocytes perpetuate the musculoskeletal deterioration in CRC survivors; and (2) to determine the effect of senescence targeting strategies on the post-cancer MSK system to regain homeostasis after external stimuli (mechanical loading and injury). To address these issues, we will study a transgenic mouse model of p16 target deletion in osteocytes (p16ocy). Twelve- and 16-month-old p16ocy mice, which reflect the human ages (50 and 65, respectively) that better mirror CRC human populations, will be submitted to a protocol for a model of murine CRC and CRC survivorship, which extends for 4 weeks of tumor induction and chemotherapy regimen, ended by surgical excision of the tumor, and followed by up to three months of morphological and functional evaluation of the MSK system. We believe that the deletion of p16 specifically in osteocytes will lead to reduced bone loss and muscle atrophy in CRC survivors and that the use of senescence targeting strategies will restore the ability of the MSK system to regain homeostasis in response to mechanical loading and injury. We believe that the findings of this project will greatly contribute to the development of strategies that prevent CRC-induced deterioration and/or accelerate the recovery of the MSK system after CRC resection and chemo cessation.